Methods for enhancing fluid flow through an obstructed vascular site, and systems and kits for use in practicing the same

ABSTRACT

Methods of enhancing fluid flow through a vascular site occupied by a vascular occlusion, as well as systems and kits for use in practicing the same, are provided. In practicing the subject methods, the vascular site is flushed simultaneously with a first dissolution fluid and a second dissolution fluid attenuating fluid, where flushing is carried out in a manner such that only a surface of the vascular occlusion is contacted with the non-attenuated dissolution fluid. Flushing is carried out in this manner for a period of time sufficient for fluid flow through the vascular site to be enhanced, e.g. increased or established. The subject methods, systems and kits for practicing the same find use in the treatment of a variety of different vascular diseases characterized by the presence of vascular occlusions, including both partial and total occlusions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.09/425,826 filed on Oct. 22, 1999 and now issued as U.S. Pat. No.6,290,689; the disclosure of which is herein incorporated by reference.

TECHNICAL FIELD

The field of this invention is vascular disease, particularly vasculardiseases characterized by the presence of vascular occlusions, includingboth partial and total occlusions.

BACKGROUND OF THE INVENTION

Vascular occlusions, which may be partial or total occlusions, play aprominent role in many types of vascular disease. Occlusions found invascular disease may vary greatly in content, and are typically complexstructures of two or more different types of components. Componentsfound in vascular occlusions include: lipids; lipoproteins; proteins;including fibrinogen, collagen, elastin and the like; proteoglycans,such as chondroitin sulfate, heparin sulfate, dermatans, etc.; cells,including smooth muscle cells, epithelial cells, macrophages andlymphocytes; and minerals, e.g. calcium phosphates such as dahllite. Anocclusion categorization system has been developed for use incharacterizing vascular occlusions, where type IV, type V and type VIlesions, as defined in Stary e tal., Arterioscler. Thromb. Vasc. Biol.(1995)15:1512-1531, are particularly relevant in vascular disease.

A variety of different protocols have been developed for use in treatingvascular diseases characterized by the presence of partial or totalocclusions. Such treatment methodologies generally involve mechanicalremoval or reduction of the size of the occlusion, and include: bypasssurgery, balloon angioplasty, mechanical debridement, atherectomy, andthe like.

Despite the plethora of different treatment strategies that have beendeveloped for the treatment of vascular diseases associated withvascular occlusions, there are disadvantages associated with eachtechnique, such as tissue damage, invasiveness, etc. For example,restenosis is a common complication that results in arteries in whichocclusions have been mechanically removed.

As such, there is continued interest in the development of endovascularmethods of treating vascular occlusions. Of particular interest would bethe development of methods and devices suitable for use in the treatmentof vascular occlusions which do not suffer from the disadvantages ofcurrently employed devices and methods.

RELEVANT LITERATURE

U.S. Patents of interest include: U.S. Pat. Nos. 4,445,892; 4,573,966;4,610,662; 4,636,195; 4,655,746; 4,690,672; 4,824,436; 4,911,163;4,976,733; 5,059,178; 5,090,960; 5,167,628; 5,195,955; 5,222,941;5,370,609; 5,380,284; 5,443,446; 5,462,529; 5,496,267; 5,785,675; and5,833,650. Multi-lumen catheter devices are described in U.S. Pat. Nos.4,329,994; 4,838,881; 5,149,330; 5,167,623; 5,207,648; 5,542,937; and6,013,068. See also: Koltun et al., Arch. Surg. (August 1987)122:901-905; Olin et al., Ann. Emerg. Med. (November 1988) 17:1210-1215;Hargrove et al., Surgery (December 1982) 92:981-993; and Rickard et al.,Cardiovascular Surg. (December 1997) 5:634-640. See also PeripheralEndovascular Interventions, 2^(nd) ed. (White & Fogarty eds., Springer,N.Y.)(1996) pp 565-576.

SUMMARY OF THE INVENTION

Methods of enhancing fluid flow through a vascular site occupied by avascular occlusion, as well as systems and kits for use in practicingthe same, are provided. In practicing the subject methods, the vascularsite is flushed simultaneously with a first dissolution fluid and asecond dissolution fluid attenuating fluid, where flushing is carriedout in a manner such that only a surface of the vascular occlusion iscontacted with the non-attenuated dissolution fluid. Flushing is carriedout in this manner for a period of time sufficient for fluid flowthrough the vascular site to be enhanced, e.g. increased or established.The subject methods, systems and kits for practicing the same find usein the treatment of a variety of different vascular diseasescharacterized by the presence of vascular occlusions, including bothpartial and total occlusions.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A & 1B provide views of a totally occluded and partially occludedvascular site, respectively.

FIG. 2A provides a representation of an aspiration catheter according ofan embodiment of the subject invention while FIG. 2B provides arepresentation of a total occlusion catheter insert for use in theaspiration catheter of FIG. 2A.

FIG. 3 provides a representation of a partial occlusion catheter insertfor use in the aspiration catheter of FIG. 2A.

FIG. 4 provides a depiction of the use of the partial occlusion cathetersystem according to the subject invention.

FIG. 5 provides a representation of a system according to the subjectinvention, which system includes a catheter device, manifold, fluidreservoirs, etc.

FIGS. 6 to 8 provides a representation of the various stages of the useof the total occlusion system of the subject invention.

FIGS. 9 and 10 provide views of alternative embodiments of the subjectmethods in which external energy is applied to the occlusion, e.g. bymovement of a guidewire as shown in FIG. 9.

FIG. 11 illustrates the limited range of the acidic dissolution fluidwhen applied according to the subject methods.

FIG. 12 provides another view of a total occlusion catheter of thecatheter systems of the subject invention.

FIG. 13 provides another view of a partial occlusion catheter of thecatheter systems of the subject invention.

FIG. 14 provides another view of an aspiration or irrigation catheter ofthe catheter systems of the subject invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Methods for enhancing fluid flow through a vascular site occupied by avascular occlusion, as well as systems and kits for use in practicingthe same, are provided. In practicing the subject methods, the vascularsite is flushed simultaneously with a first dissolution fluid and asecond dissolution fluid attenuating fluid, where flushing is carriedout in a manner such that only a surface of the vascular occlusion iscontacted with the non-attenuated dissolution fluid. Flushing is carriedout in this manner for a period of time sufficient for fluid flowthrough the vascular site to be enhanced, e.g. increased or established.The subject methods, systems and kits for practicing the same find usein the treatment of a variety of different vascular diseasescharacterized by the presence of vascular occlusions, including bothpartial and total occlusions.

Before the subject invention is described further, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

It must be noted that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise. Unless defined otherwiseall technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs.

Methods

As summarized above, the subject invention provides methods forenhancing fluid flow through a vascular site occupied by a vascularocclusion or lesion. By enhanced is meant that fluid flow is eitherestablished in situations where fluid flow is not initially present,e.g. where the target vascular occlusion is a total occlusion, orincreased where some fluid flow through the vascular site is present,e.g. in situations where the vascular site is occupied by a partialocclusion. Where fluid flow is increased, the amount or magnitude ofincrease is generally at least about 1 fold, usually at least about 5fold and more usually at least about 10 fold.

The Target Vascular Site

The target site through which fluid flow is enhanced by the subjectmethods is a site within a vessel, typically an artery or vein, andusually an artery. In many embodiments, the vascular site is aperipheral vascular site, by which is meant that the vessel in which thevascular site is located is a vessel found in one of the extremities ofthe patient to be treated, i.e. the arms or legs. Often, the vascularsite is a site in a lower extremity vessel, e.g. a lower extremityartery. Thus, of particular interest in certain embodiments areperipheral arterial vascular sites, where specific peripheral arteriesof interest include: iliac arteries, femoropopliteal arteries,infrapopliteal arteries, femoral arteries, superficial femoral arteries,popliteal arteries, and the like. In yet other embodiments, the vascularsite is present in a heart associated vessel, e.g. the aorta, a coronaryartery or branch vessel thereof, etc. In yet other embodiments, thevascular site is present in a carotid artery or a branch vessel thereof.

The vascular site is occupied by a vascular occlusion in such a mannerthat fluid flow through the vascular site, e.g. blood flow, is at leastimpeded if not substantially inhibited. By at least impeded is meantthat fluid flow is reduced by at least 20%, usually by at least 50% andmore usually by at least 80% through the vascular site as compared to acontrol. In such situations, the vascular site is occupied by a partialvascular occlusion. By substantially inhibited is meant thatsubstantially no fluid flows through the vascular site. For purposes ofthis invention, fluid flow through a vascular site is considered to besubstantially inhibited where it is not possible to pass a guidewirethrough the vascular site, where the guidewire has a diameter rangingfrom 0.014 to 0.038 in and is applied to the site with a pressureranging from about 1 to 30 oz.

A representation of a peripheral artery having a vascular site occupiedby a total vascular occlusion is provided in FIG. 1A while arepresentation of a peripheral artery having a vascular site occupied bya partial vascular occlusion is provided in FIG. 1B. In FIGS. 1A & 1B,the external iliac artery 11 is shown as it branches into the SFA 12 andthe profunda 13. Also shown are the medial circumflex and the latercircumflex, 14 and 15 respectively. The SFA is totally occluded byocclusion 16 in FIG. 1A and partially occluded by occlusion 16 in FIG.1B.

The Target Vascular Occlusion

The vascular occlusion that occupies the target vascular site isgenerally a complex structure of two or more disparate components, wheresuch components include both inorganic, e.g. calcium phosphate (such asdahllite) and organic components, including organic matter, e.g. lipids;lipoproteins; proteins; including fibrinogen, collagen, elastin and thelike; proteoglycans, such as chondroitin sulfate, heparin sulfate,dermatans, etc.; and cells, including smooth muscle cells, epithelialcells, macrophages and lymphocytes. Thrombus may also be associated withthe vascular lesion or occlusion. For example, in certain embodiments,one or both ends of the occlusion may be characterized by beingprimarily thrombotic material, e.g. a thrombus. The nature of thethrombotic domain may be organized or disorganized. As such, calcifiedocclusions that are targets of the subject methods include those thatmay be described as: type IV, type V and type VI lesions, as defined inStary et al., Arterioscler. Thromb. Vasc. Biol. (1995)15:1512-1531.

In the vascular occlusions that occupy the target vascular sites of thesubject methods, the size of the occlusion varies depending on locationand specific nature of the occlusion. Generally, the volume of theocclusion ranges from about 20 to 10,000 mm³, usually from about 30 to500 mm³ and more usually from about 50 to 300 mm³.

Flushing the Vascular Occlusion

A feature of the subject methods is that the vascular site that includesthe target vascular occlusion is simultaneously flushed with adissolution fluid and a dissolution fluid attenuating fluid. Bysimultaneously flushed is meant that both a dissolution fluid and adissolution fluid attenuating fluid are introduced to the vascular siteat the same time and fluid is concomitantly removed from the vascularsite in a manner such that only a surface of the vascular occlusion iscontacted with non-attenuated dissolution fluid and the remainder of thevascular site is contacted with attenuated dissolution fluid. Flushingis also carried out in a manner such that the overall pressure in thevascular site remains substantially constant or isometric, i.e. suchthat substantially isobaric conditions are maintained in the vascularsite during the flushing procedure.

In flushing the target vascular site according to the subject methods,the dissolution and dissolution fluid attenuating fluids (described ingreater detail infra) may be introduced into the vascular site and fluidmay be removed from the vascular site using any convenient protocol, solong as the method of fluid introduction and removal that is employedprovides for the above parameters, i.e. dissolution fluid contactlimited to a target occlusion surface and maintenance of substantiallyisobaric conditions. In many embodiments, a multi-lumen catheter basedsystem is employed to flush the target vascular site, where the catheterbased system includes at least two distinct lumens for introducing thedissolution and dissolution fluid attenuating fluids to the vascularsite and a third lumen for removal of fluid from the vascular site, i.e.for aspiration of fluid (and debris when present) from the vascularsite. Representative multilumen catheter devices and systems that can beused to practice the subject methods are described in greater detailinfra.

In flushing the target vascular sites with the dissolution fluid anddissolution fluid attenuating fluid, the fluids are introduced in amanner such that the flow rate of fluid through the vascular site of thelesion is generally at least about 10 cc/min, usually at least about 20cc/min and more usually at least about 60 cc/min, where the flow ratemay be as great as 120 cc/min or greater, but usually does not exceedabout 1000 cc/minute and more usually does not exceed about 500cc/minute, where by “volume” is meant the local environment of theocclusion or the volume of the target vascular site, as defined above.The total amount of dissolution fluid that is passed through the localenvironment of the lesion during the treatment period typically rangesfrom about 100 to 1000 cc, usually from about 200 to 800 cc and moreusually from about 400 to 500 cc. The total amount of dissolution fluidattenuating fluid that is passed through the local environment typicallyranges from about 100 to 1000 cc, usually from about 200 to 800 cc andmore usually from about 400 to 500 cc. The fluids are generallypressurized to achieve the desired flow rate, as described supra. Forexample, in embodiments in which a multilumen catheter system isemployed to deliver the fluids to the target vascular site, the pressureat the distal end of the catheter assembly through which the fluids areintroduced into the local environment typically ranges from about 50 to1200 psi, usually from about 100 to 600 psi and more usually from about200 to 400 psi. It is important to note that the overall pressure in thelocal environment is maintained at substantially isometric or isobaricconditions. As such, the negative pressure at the entrance to theaspiration means of the catheter system, e.g. the open annulus at thedistal end of the aspiration catheter in a coaxial catheter system asdescribed infra, will be of sufficient magnitude to provide forsubstantially isobaric conditions. Preferably, the overall pressure inthe local environment is maintained at a value ranging from about 0.1 to3 psi, usually from a bout 0.5 to 2.5 psi and more usually from about 1to 2 psi.

As mentioned above, the dissolution fluid and dissolution fluidattenuating fluid are introduced into the target vascular site in amanner such that only a surface of the target vascular occlusion iscontacted with non-attenuated dissolution fluid. As such, duringpractice of the subject methods, the remainder of the target vascularsite is contacted with attenuated dissolution fluid, i.e. a mixture ofdissolution fluid and dissolution fluid attenuating fluid. For example,where the target vascular occlusion is a total occlusion, the proximalsurface of the total occlusion is contacted with non-attenuateddissolution fluid while the remainder of the target vascular site, e.g.the vessel walls proximal to the total occlusion, are contacted withattenuated dissolution fluid, i.e. a fluid that is a combination of boththe dissolution fluid and the dissolution fluid attenuating fluid.

As mentioned above, in practicing the subject methods the targetocclusion is flushed with the dissolution fluid and dissolutionattenuating fluid in a manner such that the pressure in the targetvascular site, i.e. local environment which includes the surface of theocclusion, e.g. the area bounded by the vessel walls, the surface of thetarget occlusion and the catheter system used to deliver the solution,remains substantially isometric. By substantially isometric is meantthat the pressure in the local environment does not vary by asignificant amount, where the amount of variance over the treatmentperiod does not vary by more than about 50%, usually by not more thanabout 10% and more usually by not more than about 5%. In other words,the local environment remains substantially isobaric during thetreatment period. Accordingly, concomitant with fluid introduction intothe target vascular site, fluid is simultaneously removed from thetarget vascular site or local environment comprising the surface of thetarget occlusion, such that the overall volume of fluid in the targetvascular site or local environment remains substantially constant, whereany difference in volume at any two given times during the treatmentperiod does not exceed about 50%, and usually does not exceed about 10%.As such, the dissolution fluid is introduced into the local environmentof the target lesion in a manner such that the local environment remainssubstantially isovolumetric.

Time Period

The surface of the target occlusion is contacted, e.g. flushed, with thedissolution fluid according to the protocols described above for aperiod of time sufficient for fluid flow to be enhanced or establishedthrough the vascular site, e.g. established or improved. As such, wherethe target occlusion is a total occlusion, contact is maintained for aperiod of time sufficient for a guidewire to be passed through thevascular site, as described above. Alternatively, where the targetocclusion is a partial occlusion, contact is achieved for a period oftime sufficient for the rate of fluid flow to be increased through thevascular site, generally by at least about 10%, usually by at leastabout 50%, and in many embodiments by at least about 100%. Generally,the period of time during which the surface of the occlusion iscontacted with the dissolution solution ranges from about 5 to 100minutes, usually from about 10 to 30 minutes. In certain embodiments,the contact duration typically lasts for a period of time ranging fromabout 5 to 30 minutes, usually from about 10 to 30 minutes and moreusually from about 10 to 20 minutes.

Outcome

As discussed above, the subject methods result in the enhancement offluid flow through the vascular site occupied by the occlusion. Fluidflow is considered to be enhanced in those situations where the vascularsite is totally occluded when a guide wire can be moved through thevascular site without significant resistance. Fluid flow is consideredto be enhanced in those situations in which the vascular site ispartially occluded when the rate of fluid flow through the vascular siteincreases by at least 10%, usually by at least 50% and in manyembodiments by at least 100%.

In certain embodiments, the subject methods will not result in completeremoval of the target occlusion from the vascular site. As such, thevascular site, while not totally occluded, may still include lesiondeposits on the wall which impede fluid flow through the vascular siteand the removal or reduction of which is desired. Any convenientprotocol for treating these remaining deposits may be employed, e.g.balloon angioplasty, atherectomy, stenting, etc. Also of interest is theuse of two balloon catheters and an acidic dissolution solution, asdescribed in PCT/US99/15918, the disclosure of which is hereinincorporated by reference.

Of particular interest in those embodiments where the vascular site isinitially totally occluded and the partial and total occlusion catheterinserts describe infra are employed, fluid flow through the totalocclusion is first established using the catheter assembly made up ofthe total occlusion catheter insert inside the aspiration catheter.Following establishment of fluid flow, the rate of fluid flow isincreased using the catheter assembly made up of the partial occlusioncatheter insert inside the aspiration catheter.

The above described basic protocol of the subject invention may bemodified to include one or more additional steps, as described ingreater detail below under the heading “Optional Features.” However,prior to describing these representative optional features of thesubject invention, the dissolution fluid and dissolution fluidattenuating fluid elements of the subject invention will now bedescribed in greater detail.

Fluids Employed in the Subject Methods

As summarized above, in practicing the subject methods a target vascularsite is flushed with both a dissolution fluid and a dissolution fluidattenuating fluid. As such, the target vascular site is concomitantlycontacted with a dissolution fluid and a dissolution fluid attenuatingfluid. The dissolution fluid and dissolution fluid attenuating fluid arenow described separately in greater detail.

Dissolution Fluid

The dissolution fluid employed in the subject methods is one that, uponcontact with the target occlusion or lesion, serves to dissolve and/ordislodge one or more components of the target lesion in a manner suchthat fluid flow is enhanced through the vascular site, as describedabove. The nature of the dissolution may vary greatly depending on thenature of the target occlusion or lesion and the nature of the componentor components that are to be dissolved/dispersed/dislodged with thedissolution fluid. For example, the dissolution fluid may be adissolution fluid which dissolves inorganic matter, e.g. calciumphosphate minerals, such as dahllite and the like. Alternatively, thedissolution fluid may be a fluid that dissolves organic matter, e.g.structures made up of lipids, proteins, whole cells and the like. Incertain embodiments, the dissolution fluid may be one that dissolvesboth organic and inorganic matter, e.g. both calcium phosphate mineraland lipid/protein structures etc. In yet other embodiments, thedissolution fluid may be one that dissolves both organic and inorganicmatter, i.e. it may be one that includes a component that dissolvesorganic matter and a component that dissolves inorganic matter, wherethese components may be the same or different. Representativedissolution fluids are now described in greater detail individuallybelow.

Organic Matter Dissolution Fluids

Organic matter dissolution fluids include surfactant solutions, wheresurfactants of interest include both ionic, e.g. cationic, anionic (suchas soaps) and zwitterionic, and nonionic surfactants. As such, ofinterest in many embodiments are soaps and detergents. Specificsurfactants and detergents of interest include:

cationic surfactants, such as polyquaternium-10, guarhydroxypropyltrimonium chloride, laurtrimonium chloride, cetrimoniumchloride, laurtrimonium bromide, cetrimonium bromide, lauralkoniumchloride, stearalkonium chloride, trimethylglycine, ditallowdimoniumchloride, alkyl dimethyl benzylammonium chlorides and alkyltrimethylammonium methosulfate, Alkyltrimethylammonium Bromides,Cetyldimethylethylammonium Bromide, Benzalkonium Chloride,Cetylpyridinium Benzethonium Chloride, Decamethonium Bromide,Benzyldimethyldodecylammonium Bromide, DimethyldioctadecylammoniumBromide, Benzyldimethylhexadecylammonium Bromide, MethylbenzethioniumChloride, Benzyldimethyltetradecylammonium Bromide,Methyltrioctylammonium Chloride,N,N′,N′-Polyoxyethylene(10)-N-tallow-1,3-diaminopropane, and the like;

anionic surfactants, such as naturally occurring anionic surfactantcompounds or derivatives thereof, e.g. bile salts (cholic acid,dehydrocholic, deoxycholic, lithocholic, taurcholic acid, glycocholicacid, etc.,) as well as synthetic surfactants and detergents, e.g.sodium dodecyl sulfate, sodium lauroyl glutamate, sodium undecenylglutamate, sodium cetyl glutamate, lauryl phosphate, cetyl phosphate,disodium laureth-3 sulfosuccinate, sodium cocoyl isethionate, sodiumlauryl sulfate, sodium tetradecyl sulfate, sodium 2-ethylhexyl sulfate,sodium octylphenol glycolether sulfate, sodium dodecylbenzene sulfonate,sodium lauryldiglycol sulfate, ammonium tritertiarybutyl phenol andpenta- and octa-glycol sulfonates, disodium n-octyldecyl sulfosuccinate,sodium dioctyl sulfosuccinate, sodium diisooctyl sulphosuccinate, acylisethionates, acyl taurates, fatty acid amides of methyl tauride andacyl sarcosinates, Aerosol 22, Dioctyl Sulfosuccinate, Dodecyl Sulfate,Aerosol^(r)-OT, 1-Dodecansulfonic Acid, 1-Nonanesulfonic Acid, AlginicAcid*, Glycocholic Acid**, 1-Octanesulfonic Acid, Caprylic Acid,Glycodeoxycholic Acid**, 1-Pentanesulfonic Acid, 1-Decanesulfonic Acid,1-Heptanesulfonic Acid, Taurocholic Acid**, Dehydrocholic Acid**,1-Hexanesulfonic Acid, Taurodeoxycholic Acid**, Deoxycholic Acid**,N-Lauroylsarcosine, Tergitoland the like (*All acids are used as salts,usually sodium or potassium; **Bile acids), and the like;

zwitterionic surfactants, e.g. CHAPS, lauramidopropyl betaine,cocamidopropyl betaine, cocamidopropyl hydroxysultaine,cocamidopropylamine oxide, lauryl betaine, lauryl hydroxysultaine,lauraminoxide, myristamine oxide, sodium lauroamphoacetate, sodiumcocoamphoacetate and lauroamphocarboxyglycinate CHAPS⁺,N-Octadecyl-N,N-dimethyl-3-ammonio-CHAPSO⁺, 1-propanesulfonateN-Decyl-N,N-dimethyl-3-ammonio-N-Octyl-N,N-dimethyl-3-ammonio-1-propanesulfonate,1-propanesulfonate N-Dodecyl-N,N-dimethyl-3-ammonio-Phosphatidylcholine,1-propanesulfonateB-Tetradecyl-N,N-dimethyl-3-ammonio-N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate,1-propanesulfonate (⁺Nondenaturing), and the like; and

non-ionic surfactants, e.g. nonoxynol-9, glycol monostearate, glycoldistearate, PEG-150 distearate, methyl gluceth-10, methyl gluceth-20,methyl glucose sesquistearate, sodium PCA, polyethoxy 20 sorbitanmonooleate, polyoxyethylene ethers and TRITON®, TERGITOL® and SURFYNOL™surfactants, BIGCHAP, Decanoyl-N-methylglucamide, n-Nonylα-D-glucopyranoside, n-Decyl-α-D-Glucopyranoside, n-Nonylβ-D-glucopyranoside, n-Decyl-β-D-Glupyranoside,Octanoyl-N-methylglucamide, n-Decyl-β-D-Maltopyranoside, n-Octylα-D-Glucopyranoside, Deoxy-BIGCHAP, n-Octyl β-D-Glucopyranoside,n-Dodecyl-β-D-Glucopyranoside, Octyl β-D Thiogalactopyranoside,n-Dodecyl-α-D-Maltoside, Octyl β-D-Thioglucopyranoside,n-Dodecyl-β-D-Maltoside, Polyoxyethylene Esters,Heptanoyl-N-methylglucamide, Polyoxyethylene Ethers,n-Heptyl-β-D-Glucopyranoside, Polyoxyethylenesorbital Esters,n-Heptyl-β-D-Thioglucopyranoside, Sorbitan Esters,n-Hexyl-β-Dglucopyranoside, n-Tetradecyl β-D-Maltoside, Igepal CA-630,Tritons, 1-Monooleoyl-rac-glycerol, Nonanoyl-N-methylgluamide,Tyloxapol, n-Undecyl β-D-Glucopyranoside, Saponin, Nonidet P-40,Digitonin, and the like; etc.

Of particular interest in certain embodiments are naturally occurringanionic surfactant compounds or derivatives thereof, e.g. bile saltssuch as cholic acid, dehydrocholic, deoxycholic, lithocholic, taurcholicacid, glycocholic acid etc., and the like. In those embodiments wherethese agents are employed in the dissolution fluid, they may be obtainedfrom any convenient source, including the patient's own gall bladder. Inother words, they may be harvested from the gall bladder, processed asdesired, e.g. to remove impurities, decrease the concentration etc, andthen employed in the subject methods.

Where the dissolution fluid contains one or more surfactants, theoverall surfactant concentration in the fluid will vary, depending onthe nature of the particular surfactant employed.

The surfactant concentration of the dissolution fluid may vary greatly,depending on the nature of the surfactant employed, the nature of thetarget lesion, etc., but is sufficient to solubilize or disperse thetarget lesion to a sufficient extent for fluid flow to be enhancedthrough the vascular site. In many embodiments, the dissolution fluid isan aqueous surfactant solution in which the concentration of thesurfactant is at least 0.01%, usually at least about 0.1%, where thesurfactant concentration may be as high as 5% or 10% or higher, butoften will not exceed about 10%.

Instead of, or in addition to, a surfactant, the dissolution solutionmay include one or more enzymes for degrading various constituents ofthe target lesion, such as proteins, lipids, lipoproteins, and the like.Suitable enzymes include those selected from lipolytic, amylolytic andproteolytic enzymes. Proteolytic enzymes (proteases) which are ofinterest include those commercially available protease enzymes soldunder the tradenames Alcalase and Savinase by Novo Industries A/S(Denmark) and Maxatase by International Bio-Synthetics, Inc. (TheNetherlands). Amylolytic (amylase) enzymes (i.e. amylases) of interestinclude, for example, alpha-amylases obtained from a special strain of Blicheniforms, described in more detail in GB 1,269,839 (Novo).Commercially available amylases include for example, Rapidase, sold byInternational Bio-Synthetics Inc, and Termamyl, sold by Novo IndustriesA/S. Lipolytic enzymes (i.e. lipases) which find use includephospholipases A, B, C, D and sphingomyelinase, and the like. Other suchagents that may be included are thrombolytic agents, e.g. urokinase,tPA, and the like.

In yet other embodiments, the organic matter dissolution fluid mayinclude one or more organic solvents, where the organic solventsemployed in the subject methods are generally biocompatible,pharmaceutically acceptable and will at least partially dissolve thelipid component of the target lesion. Any convenient organic solvent maybe employed.

Inorganic Matter Dissolution Fluids

Where it is desired to dissolve an inorganic component in the targetvascular lesion, such as calcium phosphate mineral (e.g. dahllite) foundin calcified vascular lesions or occlusions, acidic dissolution fluidsare of particular interest. A variety of different types of acidicdissolution solutions may be employed in the subject methods. The acidictreatment solutions that find use in the subject methods generally havea pH of less than about 6.5, where the pH is usually less than about 4.0and more usually less than about 3.0. In many preferred embodiments, thepH ranges from 0 to 2, and usually 0 to 1. The acidic treatment solutioncan include a number of different types of acids, where the acids may ormay not include a hydrocarbon moiety, i.e. a hydrogen bonded directly toa carbon atom. Suitable acids that lack a hydrocarbon moiety includehalogen acids, oxy acids and mixtures thereof, where specific acids ofinterest of this type include, but are not limited to, hydrochloric,nitric, sulfuric, phosphoric, hydroboric, hydrobromic, carbonic andhydroiotic acids. For such acids, the acid can be a concentrated acid,or can be diluted. Upon dilution, the concentration of an inorganic acidwill generally be from about 10 N to about 0.01 N, preferably between 5N to 0.1 N. Also of interest are acids that include a hydrocarbonmoiety, where such acids include, but are not limited to, any organicacid of one to six (C₁ to C₆) carbons in length. Organic acids of thistype include, but are not limited to, formic, acetic, propionic, maleic,butanoic, valeric, hexanoic, phenolic, cyclopentanecarboxylic, benzoic,and the like. For an organic acid, the acid can be in concentrated form,or can be diluted. The acidic treatment solution can be composed ofeither a monobasic or a polybasic acid. Acids are “monobasic” when theyhave only one replaceable hydrogen atom and yield only one series ofsalts (e.g., HCl). Acids are “polybasic” when they contain two or morehydrogen atoms which may be neutralized by alkalies and replaced byorganic radicals.

In many embodiments of the subject invention, the acid solution ishypertonic, by which is meant that the osmolarity of the solution isgreater than that of whole blood, i.e. the osomolarity is greater than300 mosmol. The solution may be rendered hypertonic by including anyconvenient component or components in the solution which provide for thedesired elevated osmolarity.

Any convenient agent that is capable of increasing the osmolarity of thesolution may be employed, where suitable agents include salts, sugars,and the like. In many embodiments, the agent that is employed to renderthe solution hypertonic is one or more, usually no more than three, andmore usually no more than two, different salts. Generally, the saltconcentration in these embodiments of the solution is at least about 100mosmol, usually at least about 200 mosmol and more usually at leastabout 300 mosmol, where the concentration may be as high as 3000 mosmolor higher, depending on the particular salt being employed to render thesolution hypertonic, where the solution may be saturated with respect tothe salt in certain embodiments. Salts that may be present in thesubject solutions include: NaCl, MgCl₂, Ringers, etc. where NaCl ispreferred in many embodiments.

Of particular interest in many embodiments is the use of a hydrogenchloride solution. In hydrogen chloride solutions that find use in thesubject invention, the concentration of HCl in the solution ranges fromabout 0.001 to 1.0 N, usually from about 0.01 to 1.0 N and more usuallyfrom about 0.1 to 1.0 N. In many embodiments, the hydrogen chloridesolution will further include one or more salts which make the solutionhypertonic, as described above. In certain preferred embodiments, thesalt is NaCl, where the concentration of NaCl in the solution is atleast 0.05 M, usually at least 0.10 M, and more usually at least 0.15 M,where the concentration may be as high as 0.25 M or higher. In certainembodiments, the solution will be saturated with NaCl.

Of particular interest are aqueous hydrogen chloride solutions thatconsist of water, hydrogen chloride and NaCl. The concentration ofhydrogen chloride in these solutions of particular interest ranges fromabout 0.01 to 1.0 N, usually from about 0.05 to 0.5 N and more usuallyfrom about 0.075 to 0.25 N. The concentration of NaCl in these solutionsof particular interest ranges from about 0.05 to 0.25 M, usually fromabout 0.05 to 0.10 M.

Dissolution Fluids that Dissolve Both Organic and Inorganic Matter

Of interest in certain embodiments of the invention are dissolutionfluids that are capable of dissolving both organic matter and inorganicmatter. In these fluids, the fluid may contain one active agent thatdissolves both organic and inorganic matter, or an first active agent(s)for dissolving organic matter and a second active agent for dissolvinginorganic matter. An example of a dissolution fluid of this embodimentsis a fluid that includes both a surfactant/detergent component and anacid, e.g. an anionic, cationic, zwitterionic or non-ionic surfactant incombination with an acidic dissolution fluid, where these components aredescribed supra.

Of particular interest in many embodiments is the use of a hydrogenchloride solution that includes a surfactant. In these embodiments, theconcentration of HCl in the solution ranges from about 0.001 to 1.0 N,usually from about 0.01 to 1.0 N and more usually from about 0.1 to 1.0N. In many embodiments, the fluid will further include one or more saltswhich make the solution hypertonic, as described above. In certainpreferred embodiments, the salt is NaCl, where the concentration of NaClin the solution is at least 0.05 M, usually at least 0.10 M, and moreusually at least 0.15 M, where the concentration may be as high as 0.25M or higher. In certain embodiments, the solution will be saturated withNaCl. The surfactant may be a cationic, anionic, zwitterionic ornon-ionic surfactant, as described supra.

Of particular interest are aqueous hydrogen chloride solutions thatconsist of water, hydrogen chloride, a cationic surfactant, e.g. sodiumdodecyl sulfate, and NaCl. The concentration of hydrogen chloride inthese solutions of particular interest ranges from about 0.01 to 1.0 N,usually from about 0.05 to 0.5 N and more usually from about 0.075 to0.25 N. The concentration of NaCl in these solutions of particularinterest ranges from about 0.05 to 0.25 M, usually from about 0.05 to0.10 M. In many embodiments, the concentration of sodium dodecyl sulfateranges from about 0.01% to 10%, usually from about 0.1% to 5.0% and isoften around 1%.

Dissolution Fluid Attenuating Fluids

As indicated above, the target vascular site is flushed in the subjectmethods with not only a dissolution fluid, such as one of the fluidsdescribed above, but also a dissolution fluid attenuating fluid. Bydissolution fluid attenuating fluid is meant a fluid that at leastreduces the ability of the one or more active agents present in thedissolution fluid to act on the target lesion, e.g. solubilize,disperse, etc. In other words, the attenuating fluid is a fluid thatserves to at least impede the ability of the dissolution fluid activeagent(s) to solubilize or disperse its target component in the targetvascular occlusion. The manner or mechanism by which the attenuatingfluid achieves this result may vary greatly depending on the activeagent that is to be modulated by the attenuating fluid. As such, thenature of the attenuating fluid may vary greatly depending on the natureof the dissolution fluid that is to be attenuated. Representativeattenuating fluids are now described in greater detail separately below.

Surfactant Attenuating Fluids

Where the active agent of the dissolution solution is a surfactant, onetype of attenuating fluid of interest is an aqueous fluid that serves toreduce the concentration of the surfactant agent to a level such thatthe rate of solubilization of lipids is reduced, if not substantiallyeliminated. Aqueous fluids of interest include water, physiologicallycompatible aqueous solutions, e.g. saline, phosphate buffered saline,sodium bicarbonate solution, and the like.

Enzyme Attenuating Fluids

In those embodiments where the active agent is an enzyme, theattenuating fluid may comprise one or more agents that reduces, if noteliminates, the catalytic activity of the enzyme. As such, theattenuating fluid may include one or more of denaturants, inhibitors,chelators, e.g. EDTA, that chelate ions necessary for enzyme activity,and the like.

Acid Attenuating Fluids

Where the dissolution fluid is an acidic dissolution fluid, theattenuating fluid is generally a pH elevating solution. By pH elevatingsolution is meant any solution that, upon combination with the acidicdissolution solution, produces a solution with an elevated pH withrespect to the acidic dissolution solution. In principle, any fluidthat, upon combination of with the acid dissolution fluid, produces asolution having a pH higher than that of the acidic dissolution fluid,may be employed, so long as the fluid is biocompatible, at least for theperiod of time that it is present in the target vascular site. The pHelevating solution should have a pH of at least about 4, usually atleast about 6 and more usually at least about 8. As such, pH elevatingfluids of interest include water, physiologically acceptable buffersolutions, etc., where in many embodiments, the pH elevating solution isa buffer solution. Representative buffer solutions of interest include:phosphate buffered saline, sodium bicarbonate and the like.

Representative Combinations of Dissolution Fluids and Dissolution FluidAttenuating Fluids

For purposes of further description of the subject invention, specificrepresentative methods are now described in greater detail.Specifically, a representative method in which a calcified vascularocclusion is flushed with an acidic dissolution fluid and a bufferattenuating fluid is described in greater detail.

Vascular Calcified Lesion

For treatment of vascular calcified occlusions, a surface of the targetvascular occlusion is flushed with an acidic dissolution fluid for aperiod of time sufficient for fluid flow to be to be enhanced throughthe vascular site. The subject methods are further characterized inthat, simultaneously with the acidic dissolution fluid, a pH elevatingfluid is also introduced into the vascular site of the target lesion,i.e. the target vascular site. A feature of the subject methods is thatboth the acidic dissolution fluid and that attenuating pH elevatingfluid are introduced to the target vascular site in a manner such thatthe acidic dissolution fluid primarily contacts the surface of thetarget occlusion, with the remainder of the target vascular site beingcontacted with fluid that has a pH which is much higher than that of theacidic dissolution fluid. In other words, the acidic dissolution and pHelevating fluids are introduced into the vascular site in a manner suchthat only the target vascular lesion is contacted with the low pH acidicdissolution fluid. As such, the remainder of the target vascular site iscontacted with a fluid that has a pH well above that of the acidicdissolution fluid, where the lowest pH to which the remainder of thetarget vascular site is subjected is not less than 4, preferably notless than 5 and more preferably not less than 6. In other words, onlythe target vascular occlusion is contacted with the low pH aciddissolution fluid while the remainder of the target vascular site iscontacted with a solution the pH of which is not less than 4, preferablynot less than 5 and more preferable not less than 6.

A representation of a target vascular site being flushed with both anacidic dissolution fluid and a pH elevating fluid according to thisembodiment of the subject methods is provided in FIGS. 4, 6 and 11. InFIG. 4, where the target lesion is a partial occlusion, a coaxialpartial occlusion catheter device is introduced into the vascular sitesuch that the balloon 46 of the partial occlusion insert 40 and theballoon 24 of the aspiration catheter 20 flank the partial occlusion 34.Acidic dissolution fluid is introduced by the plurality of ports 44 onthe partial occlusion insert. A pH elevating solution is concomitantlyintroduced through annular space 45. Fluid is then removed from thevascular site by the aspiration catheter 20 through annular space 26.FIG. 6 provides a view of a total occlusion catheter insert flushing avascular site 12 of a total occlusion 17. As can be seen in FIG. 6,acidic dissolution fluid is introduced through the central catheter andpH elevating solution is introduce via the catheter immediatelyconcentric with the center catheter. Fluid is removed from the vascularsite via the aspiration catheter, in which the central and intermediatecatheters are coaxially positioned. FIG. 11 provides a representation ofthe pH gradients which occur in the vascular site during treatmentaccording to the present invention. The darkest area represents thelowest pH. The grey area represents the highest pH, where the pH of thisarea is not lower than 4, usually not lower than 5 and preferably nolower than 6.

Where the target vascular lesion comprises a lipid component, ananalogous method in which the dissolution fluid is a surfactant fluidand the attenuating fluid is water may be employed.

Optional Features of the Subject Methods

In a number of embodiments of the subject methods, the methods in whichthe surface of the target occlusion is contacted with the dissolutionfluid may be modified to include a number of additional method steps.Additional method steps that may be present in the overall processinclude: rendering the local environment of the target occlusionbloodless, washing or rinsing the local environment of the targetocclusion, applying external energy to the target occlusion; imaging thetarget vascular site; establishing or expanding a passageway through aninitial thrombotic domain of the target occlusion; and the like. Each ofthese representative optional features is described separately below.

Rendering the Local Environment Bloodless

In many preferred embodiments, as described above, the local environmentof the target occlusion is rendered substantially bloodless prior tointroduction of the acidic dissolution fluid. Any convenient protocolfor rendering the target vascular site substantially bloodless may beemployed. For example, where balloon catheter systems are employed, suchas those described below, the balloon(s) of the assembled cathetersystem is inflated to physically isolate the local environment from theremainder of the circulatory system and then the local environment isflushed with a physiologically acceptable solution, such thatsubstantially all of the blood present in the solution is removed.Typically, a washing solution will be employed in this step of renderingthe local environment bloodless. Examples of washing solutions that mayfind use in these embodiments include: water for injection, salinesolutions, e.g. Ringer's, phosphate buffered saline, or otherphysiologically acceptable solutions. The washing solution includes ananticlotting factor in many embodiments, where anticlotting factors ofinterest include heparin and the like. The washing solution can alsocontain chelating agents.

Application of External Energy

In certain embodiments, external energy is applied to the vascular siteto promote mechanical break-up of the occlusion into particles or debristhat can be easily removed from the vascular site. Any means of applyingexternal energy to the vascular site may be employed. As such, jets orother such means on a catheter device which are capable of providingvarying external forces to the occlusion sufficient to cause theocclusion to break up or disrupt may be employed. Of particular interestin many embodiments is the use of ultrasound. The ultrasound can beapplied during the entire time of contact of the cardiovascular tissuewith the acidic treatment solution, or the ultrasound can be applied foronly part of the treatment period. In one embodiment, ultrasound isapplied for several short periods of time while the dissolutiontreatment solution is contacted with the target occlusion. There areseveral devices for the application of ultrasound to cardiovasculartissue known to those of skill in the art. See e.g. U.S. Pat.Nos.4,808,153 and 5,432,663, the disclosures of which are hereinincorporated by reference.

In such methods where external energy is applied to the occlusion inorder to disrupt or break-up the occlusion into particles or debris, theparticles or debris may range in size from about 0.01 to 4.0 mm, usuallyfrom about 0.1 to 2.0 mm and more usually from about 0.5 to 1.0 mm. Insuch instances, the method may further include a step in which theresultant particles are removed from the vascular site. Particles may beremoved from the vascular site using any convenient means, such as thecatheter of the subject invention described in greater detail infa.

Another means that may be employed to apply external energy to thelesion during the dissolution process is to use a mechanical means ofapplying external energy. Mechanical means of interest include movingstructures, e.g. rotating wires, guidewires, rotating blades or burrs,etc., which physically contact the target occlusion and thereby applyphysical external energy to the target lesion. See e.g. FIGS. 9 and 10.A catheter as disclosed in U.S. Pat. No. 5,358,472, the disclosure ofwhich is herein incorporated by reference, or analogous thereto may beemployed.

Imaging

In addition, it may be convenient to monitor or visualize the vascularsite prior to or during treatment. A variety of suitable monitoringmeans are known to those of skill in the art. Any convenient means ofinvasive or noninvasive detection and/or quantification may be employed.Such means include plain film roentgenography, coronary arteriography,fluoroscopy, including digital subtraction fluoroscopy,cinefluorography, conventional, helical and electron beam computedtomography, intravascular ultrasound (IVUS), magnetic resonance imaging,transthoracic and transesophageal echocardiography, rapid CT scanning,antioscopy and the like. Any of these means can be used to monitor thevascular site before, during or after contact with the dissolutionfluid.

In many embodiments, an imaging agent is employed, where the imagingagent may or may not be present in the acidic dissolution solution.Imaging agents of particular interest include: non-ionic imaging agents,e.g. CONRAY™, OXILAN™, and the like.

Thrombus Removal Step

The subject methods may further include a thrombus removal step, e.g.where the domain of the target occlusion is covered by a thromboticdomain, as described above. In such methods, any thrombus removal meansthat is capable of providing sufficient access of the dissolutionsolution to the surface of the target lesion may be employed. Thus,where the thrombotic domain is a disorganized domain, it may besufficient to pass increasingly larger diameter guidewires through thedomain until a passageway of sufficient width to provide access of thecatheter assembly described above to the surface of the occlusion isestablished. Alternatively, portions of the thrombotic domain may beremoved, e.g. via atherectomy methods, angioplasty methods, and thelike, where devices for performing such procedures are known to those ofskill in the art. See the patent references cited in the RelevantLiterature section, supra, which references are herein incorporated byreference.

Use of a Plurality of Solutions

In many embodiments, the subject methods include contacting the surfaceof the target occlusion with a plurality, i.e. two or more, distinctsolutions, at least one of which is a dissolution solution as describedabove. Where one or more additional distinct solutions, such as primingsolutions, washing solutions, organic phase dissolution solutions andthe like are employed, as described below, such disparate solutions aregenerally introduced sequentially to the vascular site. For example, thetarget occlusion may be contacted with the following order of solutions:(1) washing solution to render the local environment substantiallybloodless; (2) organic phase dissolution solution, e.g. detergentsolution such as cholic acid solution, to remove organic phases from thetarget lesion; (3) acidic dissolution solution to demineralize thetarget occlusion; and (4) washing solution. Other sequences of solutionapplication can also be employed. See U.S. patent application Ser. No.09/353,127, the disclosure of which is herein incorporated by reference.Generally, in any method where a plurality of different solutions arecontacted with the target occlusion, each dissolution fluid isadministered in conjunction with a corresponding dissolution fluidattenuating solution.

Additional Applications

In addition to methods of enhancing fluid flow through a target vascularsite, methods and devices are also provided for reducing the mineralcontent of non-intimal tissue, as described in copending applicationSer. No. 09/382,571, the disclosure of which is herein incorporated byreference. Specifically, the subject invention provides methods anddevices that are analogous to those disclosed in the copendingapplication, with the only difference being that the target tissue iscontacted simultaneously with both a dissolution fluid and dissolutionfluid attenuating fluid, e.g. an acidic dissolution solution and a pHelevating solution. As such, the devices are modified such that a meansfor introducing a pH elevating solution at the same time as the acidicdissolution solution to the target tissue is provided.

Catheter Devices

As mentioned above, catheter devices and systems are employed in manyembodiments of the subject invention. In many embodiments where catheterdevices are employed, the catheter devices and systems are multilumenstructures which are designed flush a vascular site with a dissolutionfluid and dissolution fluid attenuating fluid in a manner that providesfor enhancement of fluid flow through a vascular site that is at leastpartially, if not totally, occluded by a vascular lesion, particularly avascular calcified lesion. In these embodiments, the multi-lumencatheter devices comprise at least three distinct lumens, i.e. thesubject devices at least include a first, second and third lumen.

A representative multi-lumen catheter system that includes at leastthree lumens and is specifically designed for use with an acidicdissolution fluid is now described in greater detail. (Note thatanalogous systems are suitable for use with non-acidic dissolutionfluids, e.g. surfactant dissolution fluids). The first lumen ischaracterized in that it has at least an inner wall that is resistant toreaction with the dissolution fluid. For example, where the dissolutionfluid is an acidic dissolution fluid, the first lumen has at least aninner wall that is resistant to reaction with the acidic dissolutionsolution, at least for a period of time sufficient for the intended useof the catheter to be completed. More specifically, at least the innerwall of the catheter is fabricated from a material that is resistant toreaction with a solution having a pH of less than about 4, preferablyless than about 2 and more preferably less than about 1. As such, itmust be inert to a solution that has a pH from about 0 to 4.

Generally, the material from which the inner surface of the first lumenis fabricated must be resistant to reaction with the dissolution fluid,e.g. must be substantially inert with respect to the dissolution fluid,for a period of time that is at least about 10 min long, preferably atleast about 20 min long and more preferably for at least about 1 hourlong or longer. Materials of interest from which at least the innersurface of the first lumen may be fabricated include: biocompatiblepolymers, e.g. polyimide, PBAX™, polyethylene, and the like. Thethickness of the inner surface of the first lumen must be sufficient toprotect the remainder of the catheter device from any corrosive reactionwith the acidic dissolution solution that is conveyed or deliveredthrough the first lumen during use of the catheter device, as describedin greater detail infra. As such, the thickness of the inner wall istypically at least about 0.5 mm, usually at least about 0.1 mm and moreusually at least about 0.25 mm. The first lumen of the subjectmulti-lumen catheter devices is further characterized in that it iscapable of being attached in fluid communication, either directly orindirectly, with a dissolution fluid reservoir. The effective totalcross sectional area through which dissolution fluid flows during use ofthe subject devices, (i.e. the total cross-sectional areas of anyopenings present at the distal end of the first lumen less any areaoccupied by a blocking element positioned in any of the openings) issufficient to provide the requisite rate of flushing of the vascularocclusion with the dissolution fluid. Generally, the effective totalcross sectional area provided by the at least one opening at the distalend of the first lumen is at least about 0.1 mm², often at least about0.2 mm² and somtimes at least about 0.3 mm², where the total effectivecross sectional area at the distal end of the first lumen may be aslarge as 0.6 mm² or larger, but in certain embodiments will not exceedabout 0.5 mm² and in other embodiments will not exceed about 0.4 mm².

The second lumen of the subject catheter device is employed to convey ordeliver the dissolution fluid attenuating fluid, e.g. a pH elevatingfluid, such as a buffer, to a vascular site, as described in greaterdetail infra. As such, the second lumen of the subject multi-lumencatheter devices is characterized in that it is capable of beingattached in fluid communication, either directly or indirectly, with adissolution fluid attenuating fluid reservoir. The effective totalcross-sectional area of the opening at the distal end of the secondlumen, where effective total cross-sectional area is as defined above(e.g. the annular space in a coaxial embodiment, as described in greaterdetail infra), is sufficient to provide the requisite amount ofattenuating fluid to the vascular site so that any portion of thevascular site apart from the target surface of the vascular solution isnot contacted with a non-attenuated fluid, e.g. an acidic dissolutionfluid which has a pH of less than about 4, preferably less than about 5and more preferably less than about 6. Accordingly, the effectivecross-sectional area of the opening(s) of the distal end of the secondlumen is at least about 0.8 mm², usually at least about 1.4 mm² and maybe as larger as 2.2 mm² or larger, but generally does not exceed about2.0 mm² and usually does not exceed about 1.5 mm².

The third lumen of the subject multi-lumen catheter devices is anaspiration lumen. The aspiration lumen is characterized by at leasthaving a distal opening(s) with an effective total cross-sectional area(e.g. the area of the annular space in the coaxial embodiments describedinfra) that is sufficiently large to remove fluid, and debris, from thevascular site at substantially the same rate that fluid (e.g. buffersolution and acidic dissolution solution) is introduced into thevascular site during use of the device, such that the fluid pressure inthe vascular site remains substantially isobaric or isometric, where bysubstantially isobaric or isometric is meant that the fluid pressure inthe vascular site does not vary by more than about 50 mm Hg, preferablydoes not vary by more than about 10 mm Hg, and more preferably does notvary by more than about 5 mm Hg over the total flushing period.

The subject catheter devices are further characterized in manyembodiments by at least including a first vascular occlusion meanspositioned at some point proximal to the distal end of the outer surfaceof the catheter device, e.g. the outer surface of the aspirationcatheter in the coaxial embodiments described infra. By vascularocclusion means is meant any device or component that is capable ofsubstantially, and preferably completely, occluding a vessel, e.g. anartery or vein. By substantially occluding is meant that fluid, e.g.blood, flow past the occlusion means upon activation is reduced by atleast 95%, usually by at least 97% and more usually by at least 99%,where in preferred embodiments, fluid flow is reduced by 100% such thatthe fluid flow into the vascular site is substantially, if notcompletely, inhibited. Any convenient means may be employed, where avascular occlusion means of particular interest includes an inflatableballoon. Inflatable balloons are well known in the catheter art, and anyconvenient balloon configuration may be employed. While the inflatableballoon may be one that is designed to be inflated with a gas or liquid,of particular interest in many embodiments are those that are configuredto be inflated with a liquid, e.g. a pH elevating solution.

Specific Alternative Embodiments

The subject invention provides a number of distinct alternativeembodiments of the subject catheter devices and systems. One preferredspecific embodiment of interest is a coaxial embodiment, in which eachof the first, second and third lumens are coaxial. Other alternativeembodiments include embodiments in which at least one of the lumens isnot coaxial with the other lumens, as well as embodiments in which noneof the lumens is coaxial. Each of these representative alternativeembodiments is now described in greater detail below.

Coaxial Embodiments

As mentioned above, a preferred embodiment of the subject multi-lumencatheter devices is a coaxial embodiment, in which the first, second andthird lumens of the subject catheter device are coaxial. By “coaxial” ismeant that the first, second and third lumens share a common axis. Assuch, in these embodiments the first lumen is present in an elementpositioned inside the second lumen, which in turn is present in anelement positioned inside the third lumen. Generally, the first, secondand third lumens are found inside fluid delivery means which arepositioned inside one another, where the fluid delivery means are oftenelongated tubular elements. The coaxially positioned fluid deliverymeans comprising the first, second and third lumens, i.e. the first,second and third fluid delivery means, may be held in a staticrelationship with respect to one or another or may be movable withrespect to one another, such that at least one of the fluid deliverymeans, and preferably at least two of the fluid delivery means may bemoved without moving the other fluid delivery means—i.e. each of thefirst, second and third fluid delivery means may be moved independentlyof one another. Spacers or other means on the inner walls of at leastthe second and third lumens may be present to maintain the coaxialconfiguration.

In this coaxial embodiment of the subject invention, one of the lumensserves to deliver an acidic dissolution fluid, one of the lumens servesto deliver a pH elevating fluid and one of the lumens serves to removefluid from the vascular site. In other words, two of the lumens serve tointroduce fluid to the vascular site and one of the lumens serves toremove fluid from the vascular site. While any of the lumens may serveany of the above functions, generally, the first lumen which deliversthe acidic dissolution solution (i.e the one that has at least an innersurface that is substantially inert to the acidic dissolution fluid) isthe innermost lumen of the coaxial lumens of the device. As such, thefirst lumen is the lumen with the inner walls that are closest to thecenter line or axis of the coaxial catheter device.

The first lumen is generally positioned along the center line or axis ofa first elongated fluid delivery means, where the fluid delivery meansgenerally extends along the length of the catheter from its proximal todistal end. The fluid delivery means is typically tubular in shape, andmay have a variety of different cross-sectional configurations,including square, triangular, trapezoidal, circular, elliptical,irregular, and the like, where often the cross-sectional shape of theelongated tubular member is curvilinear, and more often is circular.

The design of the first fluid delivery means may vary depending on thenature of the target vascular occlusion, e.g. whether the targetvascular occlusion is a total occlusion or a partial occlusion. Thetotal occlusion first fluid delivery means, e.g. the total occlusioncatheter insert, is an elongated tubular structure, as described above,having a blunt ended, open distal end through which fluid may be flowedunder pressure. The length of the total occlusion catheter insertgenerally ranges from about 90 to 210 cm, usually from about 100 to 190cm and more usually from about 110 to 150 cm. The outer diameter of thetotal occlusion catheter insert is such that the catheter insert may beslidably positioned in the second lumen (i.e. the lumen of the secondfluid delivery means, as described infra), and typically ranges fromabout 0.4 to 2.0, usually from about 0.4 to 1.6 mm. The inner diameterof the total occlusion catheter insert typically ranges from about 0.2to 1.0, usually from about 0.25 to 1.0 and more usually from about 0.3to 1.0 mm.

Where the target occlusion is a partial occlusion, a partial occlusionfirst fluid delivery means is employed, i.e. a partial occlusioncatheter insert. The partial occlusion catheter insert differs from thetotal occlusion catheter insert in a number of ways. First, the partialocclusion catheter insert includes a balloon or analogous vesselocclusion means at its distal end, where the distance between thevascular occlusion means and the distal end of the catheter inserttypically ranges from 1 to 30 mm, usually from about 10 to 20 mm.Second, the partial occlusion vascular insert has one or more fluidintroduction ports proximal to the proximal side of the distal balloon.The diameter of the infusion ports may vary, but typically ranges fromabout 0.2 to 1.2, usually from about 0.4 to 1.0 and more usually fromabout 0.5 to 0.8 mm. Where the vascular occlusion means on the partialocclusion catheter insert is a balloon, a balloon inflation lumen isalso present in the partial occlusion catheter insert. Finally, the endof the partial occlusion catheter insert is sealed. The length of thepartial occlusion catheter insert generally ranges from about 90 to 250cm, usually from about 100 to 230 cm and more usually from about 110 to190 cm. The outer diameter of the partial occlusion catheter insert issuch that the catheter insert may be slidably positioned in the secondlumen, i.e. the lumen of the second fluid delivery means, as describedinfra. The outer diameter typically ranges from about 0.5 to 2.0. Theinner diameter of the partial occlusion catheter insert typically rangesfrom about 0.2 to 1.0, usually from about 0.25 to 1.0 and more usuallyfrom about 0.3 to 1.0 mm.

The above described partial and total catheter inserts are furthercharacterized by being capable of being attached at their proximal ends,either directly or through one or more attachment means, to a fluidreservoir, e.g. an acidic dissolution fluid reservoir and, in the caseof the partial occlusion catheter insert, a balloon inflation means. Arepresentation of a total occlusion catheter insert 30 according to thesubject invention is provided in FIG. 2B. A representative partialocclusion catheter insert is provided in FIG. 3. In FIG. 3, partialocclusion catheter insert 40 includes elongated tubular structure 42that is sealed at its distal end 48. Proximal to the distal end 48 isballoon 46, where the distance Y typically ranges from about 1 to 30 mm,usually from about 10 to 20 mm. Also depicted are infusion ports 44. Thediameter of the infusion ports may vary, but typically ranges from about0.2 to 1.2, usually from about 0.4 to 1.0 and more usually from about0.5 to 0.8 mm. Also shown is balloon inflation lumen 43, where theballoon inflation lumen has dimensions similar to those of ballooninflation lumen 23. As evidenced, the partial occlusion catheter insertincludes two lumens, a fluid introduction lumen and a balloon inflationlumen. Also visible in FIGS. 2B and 3 is second delivery means 35 whichincludes the second lumen, described in greater detail below.

The second lumen of the subject multi-lumen catheter devices is designedfor delivery of an attenuating fluid, e.g. a pH elevating solution, tothe vascular site of the target occlusion. This lumen is generallypresent in a second fluid delivery means (element 35 in FIGS. 2B and 3),where the fluid delivery means is generally an elongated tubularstructure analogous to the first fluid delivery means described supra.In the present coaxial embodiment, the dimensions of this second fluiddelivery means, i.e. second catheter insert, are such that the firstfluid delivery means or catheter insert described above (i.e. either thepartial or total occlusion catheter insert) can fit inside this secondfluid delivery means, i.e. can fit inside the lumen of the second fluiddelivery means. A further limitation is that the first fluid deliverymeans must fit inside the second fluid delivery means in a manner suchthat an annular space is formed in the second lumen which is sufficientto convey the requisite amount of pH elevating fluid to the vascularsite during use of the device. As such, the inner diameter of the secondlumen exceeds the outer diameter of the first fluid delivery means by atleast about 0.6 mm, sometimes at least about 0.9 mm and in certainembodiments at least about 1.2 mm. Accordingly, the inner diameter ofthe second fluid delivery means ranges from about 0.8 to 2.5, usuallyfrom about 0.9 to 1.9 and more usually from about 1.0 to 1.3 mm. Thesecond fluid delivery means has an open distal end which, whenpositioned around the first fluid delivery means during use, forms anannular opening through which pH elevating fluid flows out of the secondfluid delivery means and into the vascular site during use. The totaleffective cross-sectional area of the annular opening typically rangesfrom about 0.6 to 2.6, usually from about 0.8 to 1.9 and more usuallyfrom about 0.9 to 1.3 mm². The overall length of the second fluiddelivery means typically ranges from about 90 to 210, usually from about100 to 190 and more usually from about 110 to 150 cm. The second fluiddelivery means is further characterized by having a means for connectingto a pH elevating fluid reservoir, either directly or indirectly, at itsproximal end.

The first and second lumens and their respective fluid delivery meansmay be combined into integrated catheters in certain embodiments. Anexample of a total occlusion catheter unit is presented in FIG. 12 whilean example of a partial occlusion catheter unit is presented in FIG. 13.

The third lumen in this coaxial embodiment of the subject devices is theoutermost lumen, which is generally present in an elongated tubularstructure analogous to the first and second fluid delivery means, asdescribed above. The third lumen present in this third fluid deliverymeans is employed to remove fluid from the vascular site. As such, thisthird fluid delivery means is properly viewed as an aspiration catheter.The aspiration catheter is generally an elongated tubular structurefabricated from a flexible, biologically acceptable material having aballoon or analogous vessel occlusion means positioned at its distalend. The length of the aspiration catheter may vary, but is generallyfrom about 80 to 200 cm, usually from about 90 to 180 cm and moreusually from about 100 to 140 cm. The outer diameter of the aspirationcatheter is selected so as to provide for access of the distal end ofthe catheter to the vascular site via the vascular system from theremote point of entry, where the outer diameter typically ranges fromabout 1.0 to 4.0 mm (3 to 12 Fr), usually from about 1.5 to 3.0 mm (4.5to 9.0 Fr) and more usually from about 1.7 to 2.7 mm (5 to 8 Fr). Theaspiration catheter is characterized by having an open distal end, wherethe inner diameter at the open distal end is sufficient to house thefirst and second coaxial fluid delivery means, as described supra, andremove fluid from the vascular site at the desired rate, e.g. a ratethat provides for substantially isometric or isobaric pressure in thevascular site during treatment, through the resultant annular space. Theinner diameter of the third or aspiration lumen, at least at its distalend and generally along the entire length of the aspiration catheter,typically ranges from about 0.2 to 2.0, usually from about 0.25 to 1.75and more usually from about 0.35 to 1.5 mm. The total effectivecross-sectional area at its distal end, i.e. the cross-sectional area ofthe annular space at the distal end opening, typically ranges from about1.3 to 3.9, usually from about 1.3 to 3.2 and more usually from about1.3 to 2.5 mm². Also present at the distal end of the aspirationcatheter is a vessel occlusion means, where the vessel occlusion meansis usually an inflatable balloon. The balloon is one that is inflatableto a volume sufficient to substantially occlude the vessel in which theaspiration catheter is positioned, e.g. by pressing against the intimalsurface of the vessel in which the aspiration catheter is positioned.The balloon is in fluid or gaseous communication with an inflation lumenthat runs the length of the aspiration catheter and can be connected toa balloon inflation means. The inflation lumen has an inner diameterthat typically ranges from about 0.1 to 0.5, usually from about 0.2 to0.4 mm. In certain embodiments, the aspiration catheter further includesa separate guidewire lumen. When present, the guidewire lumen has adiameter ranging from about 0.2 to 1.0 mm, usually from about 0.3 to 0.6mm. Thus, the aspiration catheter includes at least two distinct lumens,i.e. an aspiration lumen (also referred to herein as the third lumen)and a balloon inflation lumen, and in many embodiments includes threedistinct lumens, i.e. an aspiration lumen, a balloon inflation lumen anda guidewire lumen. A representation of an aspiration or irrigationcatheter is provided in FIG. 14.

The aspiration catheter is further characterized by being capable ofattaching, either directly or through one or more attachment means, atits proximal end to vacuum means, e.g. a negative pressure means, wheresuch means is sufficient to provide for the desired aspiration duringuse of the device, and a balloon inflation means, where such means issufficient to inflate the balloon at the distal end of the catheter whendesired.

A representation of the aspiration catheter of the subject cathetersystems found in the subject kits is provided in FIG. 2A. In FIG. 2A,aspiration catheter 20 includes elongated tubular member 22 and balloon24 located proximal to the distal end. The distance X between the distalmost portion of the balloon 24 and the distal end of the cathetertypically ranges from about 1 to 20, usually from about 5 to 10 mm. Alsoshown is distal open end 26 through which either the partial or totalocclusion insert catheter is moved and fluid is aspirated. Balloon 24 isinflatable via balloon inflation lumen 23.

Alternative Embodiments

In an alternative embodiments of the subject invention, at least two ofthe first, second and third lumens are not coaxial. In these alternativeembodiments, the configuration of the first, second and third lumens inthe device may vary greatly. For example, the first second and/or thirdlumens may be present on separate non-coaxial fluid delivery means. Assuch, the device could be made up of three different fluid deliverymeans bundled together to produce a triple lumen catheter device.Alternatively, a single fluid delivery means could house all threelumens. In certain embodiments, two of the lumens, i.e. the first andsecond lumen, will be present on a first fluid delivery means, whichfluid delivery means is coaxially positioned within the third lumen. Thefirst or internal fluid delivery means housing the first and secondlumens may take on a variety of configurations. In one configuration,the first and second lumens terminate or open at the distal end of theinternal fluid delivery means. In other configurations, one of thelumens opens at a different area from the other lumen. In theseembodiments, the first lumen typically opens at the distal end of theinternal fluid delivery means and the second lumen opens at a siteproximal to the distal end of the internal fluid delivery means. Thesecond lumen may open up at a one or more openings proximal to thedistal end of the internal fluid delivery means. In each of theseembodiments, the internal fluid delivery means housing the first andsecond lumens is present in a third lumen which is also housed by afluid delivery means, where this fluid delivery means may be referred toas an aspiration catheter, as described above.

Other representative multilumen catheter devices that may be adapted foruse in the subject methods include those described in U.S. Pat. Nos.:329,994; 4,838,881; 5,149,330; 5,167,623; 5,207,648; 5,542,937; and6,013,068; the disclosures of which are herein incorporated byreference. Where it is desired to apply mechanical energy to the targetlesion in combination with flushing with a dissolution fluid andaspiration, a devices as disclosed in U.S. Pat. No.5,358,472, thedisclosure of which is herein incorporated by reference, or analogousthereto, may be employed.

Catherter Systems

Also provided by the subject invention are systems for practicing thesubject methods, i.e. for enhancing fluid flow through a vascular siteoccupied by a vascular occlusion. The subject systems at least includethe catheter systems as described above, a manifold, a fluid reservoirfor storing dissolution fluid, a fluid reservoir for attenuating fluidand a negative pressure means for providing aspiration or suction duringuse of the system. The systems may further include a number of optionalcomponents, e.g. guidewires, pumps for pressurizing the dissolutionfluid, and the like. See e.g. U.S. patent application Ser. No.09/384,860, the disclosure of which is herein incorporated by reference.

A representative system is provided in FIG. 5. In FIG. 5, system 50 ischaracterized by having catheter device 51 in fluid communication withthe various fluid and vacuum sources require to practice the methods asdescribed above. Specifically, the outer aspiration catheter 52 of thecatheter device 51 is in communication with a medical grad vacuumregulator and vacuum means 53 by aspiration line 53A. The central orirrigation catheter 54 of the catheter device 51 is in fluidcommunication with power injector source of acidic dissolution solution,55. The intermediate catheter of the catheter device 51 is in fluidcommunication with a source of pH elevating solution 56, e.g. PBS/Hep.Finally, syringe 57 is used to inflate the balloon of the catheterdevice via the balloon inflation line 58.

Utility

The subject devices and methods find use in a variety of differentapplications in which it is desired to enhance fluid flow, usually bloodflow, (or at least pass a guidewire through), a vascular site that isoccupied by a vascular occlusion, e.g. a partial or total occlusion. Assuch, the subject methods and devices find use in the treatment ofperipheral vascular disease, etc. The subject methods also find use inthe treatment of coronary vascular diseases. By treatment is meant thata guidewire can at least be passed through the vascular site underconditions which, prior to treatment, it could not. Treatment alsoincludes situations where the subject methods provide for larger fluidpassageways through the vascular site, including those situations wherefluid flow is returned to substantially the normal rate through thevascular site. The subject methods may be used in conjunction with othermethods, including balloon angioplasty, atherectomy, and the like, aspart of a total treatment protocol.

A variety of hosts are treatable according to the subject methods.Generally such hosts are “mammals” or “mammalian,” where these terms areused broadly to describe organisms which are within the class mammalia,including the orders carnivore (e.g., dogs and cats), rodentia (e.g.,mice, guinea pigs, and rats), lagomorpha (e.g. rabbits) and primates(e.g., humans, chimpanzees, and monkeys). In many embodiments, the hostswill be humans.

Kits

Also provided by the subject invention are kits for use in enhancingfluid flow through a vascular site occupied by an occlusion. The subjectkits at least include a catheter device or system, as described above.The kits may further include one or more additional components andaccessories for use with the subject catheter systems, including tubingfor connecting the various catheter components with fluid reservoirs,syringes, pumping means, etc., connectors, one or more guidewires,dilators, vacuum regulators, etc.

In certain embodiments, the kits further include one or more solutions,or precursors thereof, where in such embodiments the kits at leastinclude dissolution fluid, such as an acidic dissolution fluid, e.g. ahydrochloric acid solution, as described above, where the solution maybe present in a container(s), e.g. a flexible bag, a rigid bottle, etc.For kits that are to be used in methodologies in which the fluid isflushed through the local environment of the lesion, the amount ofdissolution fluid present in the kit ranges from about 0.5 to 500liters, usually from about 0.5 to 200 liters and more usually from about0.5 to 100 liters. In many embodiments, the amount of dissolution fluidin the kit ranges from 0.5 to 5 liters, usually from about 0.5 to 2.0liters and more usually from about 0.5 to 1.5 liters. Alternatively, thekit may comprise precursors of the dissolution solution for use inpreparing the solution at the time of use. For example, the precursorsmay be provided in dry form for mixing with a fluid, e.g. water, at thetime of use. In addition to the dissolution fluid or precursors thereof,the kit may further comprise one or more additional fluids (or dryprecursors thereof), such as a priming solution, a washing solution,contrast medium, and the like. In many embodiments, the kits furtherinclude at least a pH elevating solution, e.g. a buffer solution such asphosphate buffered saline.

Other elements that may be present in the subject kits include variouscomponents of the systems, including manifolds, balloon inflation means,e.g. syringes, pumping means, negative pressure means etc.

Finally, the kits include instructions for practicing the subjectmethods, where such instructions may be present on one or more of thekit components, the kit packaging and/or a kit package insert.

The following examples are offered by way of illustration and not by wayof limitation.

Expermental EXAMPLE I

In Vitro Cholesterol Dissolution

A. Introduction

In vitro experiments were performed to document the efficacy ofcholesterol dissolution using a variety of surfactants.

B. Methods

Dissolution of cholesterol was examined in different solutions of bilesalts, non-ionic, and ionic surfactants. Solutions of bile salts wereprepared as follows: 0.5% solutions of cholic, dehydrocholic,deoxycholic, lithocholic acids were made by dissolving 0.5 grams of thefree acid powders in 100 mL H₂O previously adjusted to pH=12 with sodiumhydroxide. Solutions were then adjusted to pH=7.5 with HCl. 1%surfactant solutions were made by dilution of concentrated stocksolutions: Benzalkonium chloride, nonoxynol-9, sodium dodecyl sulfate,were prepared immediately prior to use. Dissolution studies wereperformed by adding 0.1 grams cholesterol powdered crystals to 50 mLs ofthe above surfactants with agitation on a rocker table for 1 hour.Solutions were then examined under light microscopy 200×magnificationand cholesterol crystal presence or absence and crystal morphologyrecorded for each solution.

C. Results

All solutions acted as dispersive agents for cholesterol crystals.Sodium dodecyl sulfate (SDS) was the most effective in solvating as nofree crystals were observed 5 minutes after cholesterol addition.Benzalkonium chloride also appeared to dissolve most of the crystallinecholesterol although not as quickly as SDS as there were still crystalsapparent after 10 minutes with approximately 50% crystal dissolution by1 hour. Nonoxynol-9 had little or no observable effect on the crystalstructure. The bile salts were effective in dispersing the cholesterolhowever crystal morphology was only slightly changed after 1 hour insolution; crystal edges and sharply defined faces appeared to round andsoften.

D. Conclusions

These results indicate that chemical dissolution of a major organicconstituent of atherosclerotic plaque (cholesterol) is feasible usingcommon surfactants and that dispersive agents such as bile salts arealso effective in loosening plaque components for subsequent removal. Itcan also be safely extrapolated that lipid dissolution is readilyachievable based on solubility data for lipids versus cholesterol.

EXAMPLE II

In Vitro Thrombus Removal

A. Introduction

In vitro experiments were performed to document the efficacy of thrombusremoval using the common surfactant sodium dodecyl sulfate.

B. Methods

Fresh cadaveric femoral arteries which contained soft clots partiallyoccluding the vessel lumen were used. Flow was significantly reduced inall vessel segments prior to treatment with SDS as demonstrated by theinability to inject saline through the vessel using a 25 cc syringe.

Vessels were treated with a 1% surfactant solution of sodium dodecylsulfate (SDS, Sigma chemicals), prepared immediately prior to use.Treatment consisted of injection of surfactant through a 35 cc male luersyringe and flow characteristics recorded.

C. Results

SDS was effective in removing soft thrombus from occluded femoralarteries. Flow was reestablished in all samples and segments of clotwere visible in the effluent of the flushed vessels. Approximately 60 ccof surfactant solution was used per treatment over a 10 minute interval.

D. Conclusions

These results indicate that chemical removal of an organic constituentof atherosclerotic plaque (thrombus) is feasible using commonsurfactants and that some portions of clot may be dispersed forsubsequent removal.

III. Demineralizing a Calcified Aorta

A. Materials

A human heart with an attached aorta and corotid artery branches wasobtained and characterized flouroscopically for the presence ofmineralization. The mineralized deposits are radio-opaque and arewell-established to be the calcium phosphate mineral carbonated apatite(dahllite) [see Tomasic 1994 In: Brown and Constantz, Hydroxyapatite andRelated Materials CRC Press]. Physical manipulation of the tissueindicated that the mineral makes the vessel rigid and the walls of thevessel are hard. Extensive mineralization was seen in the aorta and thethree corotid artery branches. Two of the three side branches of thebrachial-cephalic corotid artery were completely occluded withmineralization. The other two corotid artery branches were partiallyoccluded with mineralization.

B. Experimental Set-up

The distal and proximal ends of the aorta were cannulated and tubing wasattatched. The distal outflowing tube has a “Y” to allow the exfluentsolution to flow into two different collection traps: one fordemineralizing solution, the other for saline wash. The reason for thisdesign is that the calcium concentration is measured in the exfluentdemineralizing solution so it needs to be isolated from the occasionalsaline wash to remove contrast media. An infusion catheter was placedthrough the wall of the proximal tubing and advanced into the aorta tojust proximal of the brachio-cephalic corotid branch point. The exfluentports of the unoccluded corotid arteries and the distal aotric tube wereclipped off with hemostats and contrast media was infused into theinfusion catheter under fluoroscopy, filling the aorta with radio-opaquecontrast media. The extent of occlusion was quantified fluoroscopically.The hemeostats were then unclipped and the system was flushed withsaline.

C. Demineralization

4 liters of 1N hydrochloric acid with 0.25 mole/liter sodim chlorideconcentration were infused through the infusion catheter by drawing thedemineralizing solution into 60 ml syringes with lure-lock cannulae,attaching them to the infusion catheter and injecting at a rate rangingbetween 125 and 250 ml/minute. Four successive infusion segments wereperformed:

0-5 minutes

5-10 minutes

10-15 minutes

15-20 minutes

Between each five minute infusion the system was flushed with saline,the open exfluent ports were clipped with hemostats, radio-opaquecontrast media was infused and the extent of mineralization quantifiedfluoroscopically. Following this evalution the hemostats were unclippedand the system flushed with saline and the next infusion begun.

D. Results

By the end of the experiment when all four liters of demineralizingsolution had been infused, all three totally occluded sub-branches ofthe brachiocephalic corotids artery had been opened and solution flowedfrom their distal ports.

1. 0-5 minutes (approximately 550 ml)

The solution flowed out of the two partially occluded corotid arteriesand the distal aortic tube was clipped off. About 2 minutes into theinfusion, solution began dripping from the totally occludedbrachio-cephalic segments. When the collected exfluent demineralizingsolution was observed, removed solids were collected in a 50 mlcentrifuge vial; approximately 20 ccs of solid white material waspresent. The radio-contrast at 5 minutes showed the occluded arteriesopening up and the lumen of all the arteries opening. The general extentof mineralization was also noticeably diminished.

2. 5-10 minutes (approximately 1 liter)

Now the most open corotid artery was clipped off, the partially occludedcorotid artery was half clipped off, allowing limited out flow and thedistal aortic tube was totally clipped-off. Flow progressively increasedfrom the brachio-corotid arteries and two of the three sub-segmentsbegan flowing substantially, as did the partially occluded third corotidartery. Radio-contrast imaging at 10 minutes corroborated the flowobservations, showing the arterial lumen had considerably opened toallow flow.

3. 10-15 minutes (approximately 1 liter)

Now both open corotid arteries were clipped off, allowing limited outflow through the brachial-cephalic corotid artery and the distal aortictube was totally clipped-off. Flow progressively increased from thebrachio-corotid artery and two of the three sub-segments began flowingsubstantially and third sub-segment began flowing somewhat.Radio-contrast imaging at 15 minutes corroborated the flow observations,showing the arterial lumen had considerably opened to allow flow.

4. 15-20 minutes (approximately 1.5 liters)

Now both open corotid arteries were clipped off as well as the twoflowing brachio-cephalic sub-segments, allowing limited out flow throughone the brachial-cephalic sub-segment that was most occluded at thebeginning and was still only flowing in a restricted fashion. The distalaortic tube was totally clipped-off. Flow progressively increased fromthe brachio-corotid sub-segment and began flowing to the extent that theflow squirted off the table onto the floor. Radio-contrast imaging at 20minutes treatment corroborated the flow observations, showing thearterial lumen had considerably opened to allow flow.

E. Conclusion

By the end of the experiment, a heavily calcified aorta and corotid treewas substantially demineralized and flow re-established. The arotachanged from being hard to soft and resiltiant to the touch. Thevascular tissue showed no mechanical loss of strength of flexiblebehavior.

EXAMPLE IV

Solution Containing Surfactant and Acid Components

A solution of sodium dodecyl sulfate (SDS) (a.k.a. sodium laurylsulfate) (1%) and 0.1N hydrochloric acid (pH 1.0) made isotonic (300mOsmol) with sodium chloride was prepared and compared with a solutionof sodium dodecyl sulfate solution (1%). It was found that the sodiumdodecyl sulfate solution and the sodium dodecyl sulfate/hydrochloricacid solution adjusted to pH 1.0 formed micelles around cholesterolcrystals making the cholesterol crystals water soluble. These resultsindicate that an detergent/acid combination solution can be used todissolve/remove both the mineral and organic components of a plaquesimultaneously. Addition of the detergent to the hydrochloric acidsolution does not affect the ability of the solution to dissolve mineralor the surfactant to dissolve the organic matter by forming micelles.This combination solution can be buffered with sodium bicarbonate(NaHCO₃) in the same manner that the hydrochloric acid solution isbuffered with NaHCO₃, as described in the specification supra.

EXAMPLE V

pH Gradient Study

Materials/Method

An Orion Needle-Tip electrode was used to measure pH. A 10 cm piece of¼″ ID Tygon tubing served as a vessel model. A hemostat was used toligate the tubing to mimic a total occlusion. The pH electrode wasinserted horizontally through the wall of the tubing just proximal tothe ligation and pH measurements were made in the center of the tube andat both walls. The Corazon Total Occlusion Catheter/Aspiration Cathetersystem was inserted at the open end of the Tygon tubing and advanced tothe pH electrode. The distance between the tip of the Total OcclusionCatheter and the tip of the Aspiration catheter was set at 5 mm. CDS wasirrigated using a Medrad at 0.35 mL/s. Buffer was irrigated using anEndoflator (inflation device) at a pressure of 50-100 psi giving a flowrate of 0.22 mL/s. Aspiration was set at 150 torr. Initially, thedistance between the catheter and the electrode, referred to as D, was 0mm. Measurements were made at D=0, and then the catheter/aspirationsystem was withdrawn until the distance from the electrode was D=3 mm.Measurements were made for D=0, 3, 6, 9, 12, and 15 mm.

Results/Conclusion

The pH gradients measured are shown in the figure below. The numbersbelow represent an average of the pH values measured at that particulardistance D from the tip of the catheter. The pH levels measured at thewall of the vessel are very similar on both sides

The figure shows that the pH rises as the distance from the tip of thecatheter increases. The pH levels appear to reach an asymptote at adistance of about 9 mm from the tip of the catheter in both the centerof the tube and at the walls. We have determined that cell hemolysisbegins at around pH 4.0. The pH measurements taken at the walls of thetubing indicate that the walls are sufficiently buffered at alldistances D. The dissolution of carbonated hydroxyapatite (CHA) occursat a reasonable rate (˜5 mg/min) at pH's below 1.3. Therefore, the tipof the catheter should be placed directly on CHA for dissolution, or atleast proximal thereto.

EXAMPLE VI

Safety

The following experiment was performed to evaluate the Safety andFeasibility of calcium demineralization solution via local deliverysystem in the peripheral arterial system.

Safety was evaluated in terms of:

1) systemic response and toxicity (serum indices for renal and liverfunction, acid-base balance, blood chemistry and blood clotting factorsif necessary)

2) cellular response of the treated vessel to both the demineralizingsolution and the catheter delivery system.

3) end organ toxicity and tissue response via histopathology analysis ofheart, liver, and kidneys.

Feasibility was assessed in terms of the following quantitative andqualitative assessments:

1) anatomical and morphological characteristics of the vessels viaimaging angiography and intravascular ultrasound

2) functional measure of blood flow through the treated vessel assessedvia transonic flow probe.

Methods: Canines were treated with Corazon Technologies' DecalcificationSystem, Peripheral Arterial Catheter. This system is designed tosimultaneously deliver two solutions: a demineralizing solution and abuffer. A third lumen is used to aspirate the resulting mixture. Animalswere randomly chosen and treated according to the following technique:(1) Bilateral exposure of the animal's femoral arteries, (2) Introducerand catheter insertion via an 8.5 Fr carotid puncture, advancing to leftor right femoral artery (randomly chosen), (3) Temporary vessel loopligature on distal femoral artery to represent total occlusion (4)“treatment” of total occlusion using demineraling solution and buffer,(5) removal of vessel loop, (6) repositioning of catheter to remainingfemoral artery, (7) Temporary vessel loop ligature on distal femoralartery to represent total occlusion (8) treatment of total occlusionusing saline (control), (9) removal of vessel loop, and (10) surgicalclosure and recovery of animal. Animals were recovered for 30, 60, or 90days.

Results: Eight dogs were treated. Six animals were sacrificed at 0, 30(n=3), 37, and 60 days. Microscopic pathology analysis indicates nodifference between treated vessels and controls. Systemic and organstudy results are pending. Noninvasive test results (ultrasound) ofother surviving dog arteries indicate bilateral patent vessels.

EXAMPLE VI

Representative Treatment Protocol

A. A 50 year old male having a total occlusion in the superficialfemoral is treated as follows.

1. The patient is heparinized using standard procedures.

2. An introducer sheath is placed either in the same leg to provideretrograde access or in the opposite leg to provide cross-over access.

3. A guidewire is inserted and advanced to the site of the totalocclusion.

4. The catheter device is inserted so that the distal end of the deviceis at the vascular site occupied by the total occlusion. The balloon isthen inflated by depressing the syringe, such that the balloon occludesthe vessel proximal to the occlusion. See FIG. 6.

5. Contrast medium is then injected into the vascular site to confirmthe location of the distal end of the catheter and the inflated balloon.

6. A sufficient amount of heparinized phosphate buffered saline is theninjected through port into the isolated vascular site or localenvironment and aspirated therefrom such that the isolated localenvironment is rendered substantially bloodless.

7. The surface of the total occlusion is then flushed with both anacidic dissolution fluid A (0.1N HCl, 0.05 M NaCl) and a phosphatebuffered saline solution at the same time as shown in FIG. 6.

8. As the occlusion is demineralized, the catheter insert is advancedindependent of the aspiration catheter and buffer catheter.

9. Where desired, the balloon may be deflated, the entire devicerepositioned, and then balloon may be reinflated to move the distal endof the total occlusion catheter insert to a site further into theocclusion. See FIGS. 7 and 8.

10. Once a passage through the occlusion sufficient to pass a guidewirethrough the occlusion is produced, the device is removed.

11. The above procedure results in fluid flow through the vascular siteoccupied by the lesion being reestablished, as evidenced by passing aguidewire through the vascular site.

12. Where desired, following reestablishment of fluid flow through thetotal occlusion, the total occlusion catheter insert is removed. Aguidewire is then inserted through the large lumen of aspirationcatheter 20 to a space beyond the distal end of the occlusion. A partialocclusion catheter insert is then introduced over the guidewire to aposition such that the balloon at the distal end of the insert is on thefar side of the partial occlusion. The vascular site is then flushed asshown in FIG. 4 until the desired amount of lesion dissolution isachieved.

B. Variations on the Above Procedure

The above procedure is performed with the additional step of applyingmechanical energy to the occlusion during flushing with the acidicdissolution solution. FIG. 9 shows mechanical energy being applied tothe occlusion by contacting a guidewire 91 with the surface of the totalocclusion during flushing. FIG. 10 shows mechanical energy being appliedto the surface of the occlusion with the proximal end of the totalocclusion insert. Other means of applying external energy, e.g.mechanical energy, may also be employed.

It is evident from the above discussion and results that improvedmethods of enhancing blood flow through a vascular occlusion areprovided. Specifically, the subject invention provides a means forreadily establishing fluid flow through a vascular site totally occludedby a calcified vascular occlusion, which has heretofore been difficultto practice. As such, the subject invention provides a means for usingless traumatic procedures for treating peripheral vascular disease,thereby delaying or removing the need for graft procedures and/oramputation. A critical feature of the subject devices and methods isthat only the target occlusion is subjected to the low pH conditions ofthe acidic dissolution solution. As such, unwanted contact of otherportions of the target vascular site and/or host are avoided. Thisability to employ concentrated dissolution fluids provides for a safeprocedure that exhibits low toxicity. This ability to employconcentrated dissolution fluids also provides for a rapid procedure. Assuch, the subject invention represents a significant contribution to thefield.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A method of enhancing fluid flow through avascular site occupied by a vascular occlusion, said method comprising:simultaneously flushing said vascular site with: (i) a dissolutionfluid; and (ii) a dissolution fluid attenuating fluid; for a period oftime sufficient for fluid flow to be enhanced through said vascularsite; with the proviso that said simultaneous flushing occurs in amanner such that only a surface of said vascular occlusion is contactedwith non-attenuated dissolution fluid and the remainder of said vascularsite is not contacted with non-attenuated dissolution fluid; wherebyfluid flow is enhanced through said vascular site.
 2. The methodaccording to claim 1, wherein said vascular occlusion at least comprisesorganic matter.
 3. The method according to claim 1, wherein saidvascular occlusion at least comprises inorganic matter.
 4. The methodaccording to claim 1, wherein said vascular occlusion comprises bothorganic and inorganic matter.
 5. The method according to claim 1,wherein said dissolution fluid is an organic matter dissolution fluid.6. The method according to claim 5, wherein said organic matterdissolution fluid comprises an active agent selected from the groupconsisting of enzymes, surfactants and thrombolytic agents.
 7. Themethod according to claim 1, wherein said dissolution fluid is aninorganic matter dissolution fluid.
 8. The method according to claim 7,wherein said inorganic matter dissolution fluid is an acidic dissolutionfluid.
 9. The method according to claim 1, wherein said occlusion is atotal occlusion.
 10. The method according to claim 1, wherein saidocclusion is a partial occlusion.
 11. The method according to claim 1,wherein a catheter device is used to flush said surface of said vascularocclusion.
 12. The method according to claim 1, wherein said catheterdevice comprises at least three different lumens.
 13. A kit for use inenhancing fluid flow through a vascular site occupied by a vascularocclusion, said kit comprising: a means for flushing said vascular sitewith a dissolution fluid and a dissolution fluid attenuating fluid; andinstructions for practicing the method of claim
 1. 14. The kit accordingto claim 13, wherein said kit further comprises a dissolution fluid or aprecursor(s) thereof.
 15. The kit according to claim 13, wherein saidkit further comprises a dissolution fluid attenuating fluid orprecursors thereof.
 16. The kit according to claim 13, wherein said kitfurther comprises a guidewire.
 17. A method of enhancing fluid flowthrough a vascular site occupied by an organic matter comprisingvascular occlusion, said method comprising: simultaneously flushing saidvascular site with: (i) an organic matter dissolution fluid; and (ii) anorganic matter dissolution fluid attenuating fluid; for a period of timesufficient for fluid flow to be enhanced through said vascular site;with the proviso that said simultaneous flushing occurs in a manner suchthat only a surface of said organic matter comprising vascular occlusionis contacted with non-attenuated organic matter dissolution fluid andthe remainder of said vascular site is not contacted with non-attenuatedorganic matter dissolution fluid; whereby fluid flow is enhanced throughsaid vascular site.
 18. The method according to claim 17, wherein saidorganic matter dissolution fluid comprises an active agent selected fromthe group consisting of enzymes, surfactants and thrombolytic agents.19. The method according to claim 18, wherein said organic matterdissolution fluid comprises a surfactant.
 20. The method according toclaim 19, wherein said organic matter dissolution fluid attenuatingagent is an aqueous fluid.
 21. The method according to claim 18, whereinsaid organic matter dissolution fluid comprises an enzyme.
 22. Themethod according to claim 21, wherein said organic matter dissolutionfluid attenuating agent comprises an agent that reduces the activity ofsaid enzyme.
 23. The method according to claim 22, wherein said enzymeactivity reducing agent is selected from the group consisting of adenaturant and an inhibitor.
 24. The method according to claim 18,wherein said vascular occlusion is a total occlusion.
 25. The methodaccording to claim 18, wherein said vascular occlusion is a partialocclusion.
 26. A method of enhancing fluid flow through a vascular siteoccupied by an inorganic matter comprising vascular occlusion, saidmethod comprising: simultaneously flushing said vascular site with: (i)an inorganic matter dissolution fluid; and (ii) an inorganic matterdissolution fluid attenuating fluid; for a period of time sufficient forfluid flow to be enhanced through said vascular site; with the provisothat said simultaneous flushing occurs in a manner such that only asurface of said inorganic matter comprising vascular occlusion iscontacted with non-attenuated inorganic matter dissolution fluid and theremainder of said vascular site is not contacted with non-attenuatedinorganic matter dissolution fluid; whereby fluid flow is enhancedthrough said vascular site.
 27. The method according to claim 26,wherein said inorganic matter is a calcium phosphate mineral.
 28. Themethod according to claim 26, wherein said inorganic matter dissolutionfluid is an acidic solution.
 29. The method according to claim 28,wherein said inorganic matter dissolution fluid attenuating fluid is abuffer solution.
 30. The method according to claim 26, wherein saidvascular occlusion is a total occlusion.
 31. The method according toclaim 26, wherein said vascular occlusion is a partial occlusion.
 32. Amethod of enhancing fluid flow through a vascular site occupied byvascular occlusion, said method comprising: simultaneously flushing saidvascular site with: (i) a dissolution fluid that dissolves both organicand inorganic matter; and (ii) dissolution fluid attenuating fluid; fora period of time sufficient for fluid flow to be enhanced through saidvascular site; with the proviso that said simultaneous flushing occursin a manner such that only a surface of said vascular occlusion iscontacted with non-attenuated dissolution fluid and the remainder ofsaid vascular site is not contacted with non-attenuated dissolutionfluid; whereby fluid flow is enhanced through said vascular site. 33.The method according to claim 32, wherein said dissolution fluidcomprises an acid.
 34. The method according to claim 32, wherein saiddissolution fluid comprises a surfactant.
 35. The method according toclaim 32, wherein said dissolution fluid attenuating fluid is a buffersolution.
 36. The method according to claim 32, wherein said vascularocclusion is a total occlusion.
 37. The method according to claim 32,wherein said vascular occlusion is a partial occlusion.